tumor-suppressor functions of the tp53...

Tumor-Suppressor Functions of theTP53 Pathway

Brandon J. Aubrey,1,2,3 Andreas Strasser,1,2 and Gemma L. Kelly1,2

1The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia2Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia3Department of Clinical Haematology and Bone Marrow Transplant Service, The Royal MelbourneHospital, Parkville, Victoria 3050, Australia

Correspondence: [email protected]; [email protected]

The fundamental biological importance of the Tp53 gene family is highlighted by its evolu-tionary conservation for more than one billion years dating back to the earliest multicellularorganisms. The TP53 protein provides essential functions in the cellular response to diversestresses and safeguards maintenance of genomic integrity, and this is manifest in its criticalrole in tumor suppression. The importance of Tp53 in tumor prevention is exemplified inhuman cancer where it is the most frequently detected genetic alteration. This is confirmed inanimal models, in which a defective Tp53 gene leads inexorably to cancer development,whereas reinstatement of TP53 function results in regression of established tumors that hadbeen initiated by loss of TP53. Remarkably, despite extensive investigation, the specificmechanisms by which TP53 acts as a tumor suppressor are yet to be fully defined. Wereview the history and current standing of efforts to understand these mechanisms andhow they complement each other in tumor suppression.

The TP53 protein is a critical tumor suppres-sor that plays a fundamental and multifa-

ceted role in the development of cancer andcancer therapy. Despite more than 30 years ofvigorous research and an expansive body ofliterature, the precise molecular mechanismunderlying TP53’s tumor-suppressor functionhas not been defined and remains the focus ofactive investigation. Understanding the tumor-suppressor function of the Tp53 gene will notonly have profound importance to the under-standing of cancer biology but will likely havean impact on cancer therapy and preventionthrough improved exploitation of wild-type

Tp53 functions as well as gained insight intospecific vulnerabilities imposed on tumors byloss of TP53 function. The TP53 protein exertseffector functions that impact on virtually all ofthe hallmark features of cancer (Hanahan andWeinberg 2011); however, it is still not clearwhich of these functions is essential to its po-tent tumor-suppressor function and how thesefunctions interact. Indeed, it is becoming in-creasingly apparent that multiple pathways arelikely to collaborate in exerting this tumor-sup-pression function and that the TP53 protein hascontext-specific roles. Here we discuss the func-tioning of the TP53 protein as a tumor suppres-

Editors: Guillermina Lozano and Arnold J. Levine

Additional Perspectives on The p53 Protein available at www.perspectivesinmedicine.org

Copyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a026062

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sor and review efforts to understand the under-lying mechanisms.

THE TUMOR-SUPPRESSOR TP53 PROTEIN

The TP53 protein was first discovered in 1979through its association with simian virus 40(SV-40) large T antigen in virally transformedcancer cells (DeLeo et al. 1979; Lane and Craw-ford 1979; Linzer and Levine 1979). For the firstdecade following its discovery, the TP53 pro-tein was considered to be encoded by a proto-oncogene because of its effect on increasing cellgrowth and survival when forcibly expressedin cell lines. It is now known that this initialresearch describing TP53 function was inadver-tently performed on mutant Tp53 genes ratherthan the wild-type form (Levine and Oren2009). The realization of its role as a tumorsuppressor came from a number of importantobservations. In 1989, the Tp53 gene was iden-tified as the target of the frequently re-occurring17p chromosomal deletion observed in humancolorectal carcinoma (Baker et al. 1989) with.50% of these tumors harboring missense mu-tations in the remaining Tp53 allele. The highfrequency of Tp53 inactivation strongly suggest-ed its tumor-suppressor function. Moreover, inthe same year, it was shown that enforced ex-pression of the wild-type TP53 protein couldblock oncogene-mediated transformation ofprimary rat embryonic fibroblasts in culture(Eliyahu et al. 1989; Finlay et al. 1989).

The role of the TP53 protein in tumor sup-pression has been experimentally proven andfurther examined using mouse models generat-ed by gene targeting. Confirming the tumor-suppressor function of the Tp53 gene, Tp53knockout (Tp532/2) mice and mice with loss-of-function mutations in Tp53 develop sponta-neous tumors with 100% incidence by 9 mo ofage (Donehower et al. 1992; Jacks et al. 1994;Lang et al. 2004; Olive et al. 2004). Interestingly,the genetic background influences the tumorspectrum: Tp532/2 mice on a C57BL/6 back-ground mostly develop thymic lymphoma,whereas sarcomas, hemangiomas, B-cell lym-phomas, and breast cancers can arise on 129SV,BALB/c, or mixed genetic backgrounds (Harvey

et al. 1993a; Jacks et al. 1994; Nacht et al.1996). The Tp532/2 mice also have an increasedsusceptibility to carcinogen and g-irradiation-induced tumor development (Harvey et al.1993b; Kemp et al. 1994), consistent with thecritical role of the TP53 protein in the cellularresponse to DNA damage. Inactivation of theTP53 pathway can also markedly accelerate on-cogene-driven tumor development (Eischenet al. 1999; Schmitt et al. 1999; Michalak et al.2009). In addition to preventing spontaneoustumor formation, the TP53 protein exerts astrong tumor-suppressive effect in establishedTP53-deficient tumors. Inducible restorationof the wild-type TP53 protein in establishedtumors that had been elicited by loss of TP53function leads to tumor regression and pro-longed survival of tumor-burdened mice (Mar-tins et al. 2006; Ventura et al. 2007; Xue et al.2007). Interestingly, functional TP53 restorationin such tumors in vivo shows dramatic contextdependence, with induction of apoptosis inlymphomas but cellular senescence in sarcomas.This may relate to the type of transformedcells or the nature of the oncogenic lesions thatdrove their transformation (in addition to lossof TP53) (Junttila et al. 2010). Regardless, thesestudies affirmed the TP53 tumor-suppressorfunction in vivo.

The importance of the Tp53 gene as a tu-mor suppressor is highlighted in human cancerwhere it is the most commonly mutated gene,with mutations found in a broad variety of can-cer types (Vogelstein et al. 2000; Petitjean et al.2007). Furthermore, in cancers in which theTp53 gene remains intact, TP53 function is of-ten impaired, for example, by interference fromviral proteins or up-regulation of negative regu-lators, such as the E3 ubiquitin ligase, MDM2(called HDM2 in humans) (Vogelstein et al.2000). Thus, most human cancers contain a ge-netic or epigenetic alteration that impairs theTP53 pathway.

The requirement for normal TP53 functionin tumor suppression is evident in families withthe Li–Fraumeni syndrome, which are proneto spontaneous tumor formation (Li and Frau-meni 1969) owing to the inheritance of a germ-line loss-of-function mutation in one Tp53

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allele (Malkin et al. 1990; Srivastava et al. 1990).Li–Fraumeni syndrome patients typically de-velop cancer before the age of 45 yr, whichmost often presents as a soft tissue or bony sar-coma, breast cancer, brain tumor, adrenal cor-tical carcinoma, or leukemia. However, withlarger epidemiological studies, it is now appar-ent that affected families may have a muchbroader range of malignancies and age of onset,with rare individuals even remaining tumor freeand experiencing longevity, highlighting thecomplexity of the TP53 tumor-suppressor net-work (Kamihara et al. 2014). In an informativeexample, a cluster of cases of childhood adrenalcortical carcinoma observed in Southern Brazil(Ribeiro et al. 2001; Achatz et al. 2007) led to thediscovery of a mutation, R337H, that results inpH-dependent instability of the TP53 tetramer(DiGiammarino et al. 2002) and tissue-restrict-ed tumor development. The study of humandisease continues to provide important insightinto the function of the TP53 protein.

The accumulated knowledge of the TP53tumor-suppressor function from more than30 yr of research has culminated in its exploi-tation for the treatment of human cancer. Tar-geted therapies aimed at specifically increasing,or restoring, TP53 function have proven effec-tive in eliciting tumor regression in preclinicalmodels, for example, by using small moleculeinhibitors that block the E3 ubiquitin ligase,MDM2 (HDM2), which is the major negativeregulator of TP53 (Vassilev 2005; Brown et al.2009).

REQUIREMENTS FOR TP53-MEDIATEDTUMOR SUPPRESSION

Detection and Response to Oncogenic Stress

The TP53 tumor suppressor can be activated bydiverse cellular stresses, including oncogene ex-pression, DNA damage, hypoxia, metabolic dys-function, and replicative stress, following whichit implements appropriate responses to opposecancer initiation. Activation of the TP53 proteinmay result in a variety of cellular responses, in-cluding apoptosis, cell senescence, cell-cyclearrest, DNA repair, metabolic adaptations, and

changes to cellular characteristics, such as differ-entiation state. The fate of the cell followingTP53 activation is determined by the type, du-ration, and amplitude of the stress signal as wellas the context in which it occurs, such as the celltype. The outcome is modulated by the interplaywith other signaling pathways that are active. Inaddition, the TP53 protein exerts substantialcontrol over cellular homeostasis in the steadystate, even before “activation” by stress signals.Control of TP53 activity is achieved through anelaborate system of posttranslational modifica-tions, including phosphorylation, acetylation,and ubiquitination, which impact TP53 proteinbinding to specific sites in the DNA, proteinturnover, and interaction with other proteinsthat affect TP53 protein transcriptional func-tion (Kruse and Gu 2009). Furthermore, theremay be an additional role for the regulation ofTP53 protein activity according to the levels andsites of Tp53 gene expression. The TP53 protein,therefore, lies at the convergence of a diverserange of signaling processes that communicatethe cell state (Fig. 1). These signals are then in-tegrated to elicit a protective TP53-mediated re-sponse; the dynamic regulation and activationof TP53 protein function is critical for effectivetumor suppression.

Tumor Suppression and TranscriptionalRegulation

Following activation, the TP53 protein func-tions predominantly as a transcription factor(Riley et al. 2008). The TP53 protein forms ahomotetramer (Friedman et al. 1993) that bindsto specific Tp53 response elements in genomicDNA (el-Deiry et al. 1992; Cho et al. 1994) todirect the transcription of a large number ofprotein-coding genes (Riley et al. 2008). Therequirement for TP53 transcriptional activityin tumor suppression has been examined by sys-tematically mutating the transactivation do-mains of the TP53 protein, rendering it eitherpartially or wholly transcriptionally defective(Brady et al. 2011; Jiang et al. 2011). Impor-tantly, mutations resulting in complete loss ofTP53 transcriptional activity ablate its ability toprevent tumor formation, supporting the con-

Tumor-Suppressor Functions of TP53 Pathway

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cept that transcriptional regulation is centralto the tumor-suppressor function. Nontran-scriptional functions for the TP53 protein havebeen proposed; however, their biological impor-tance remains uncertain (Vousden and Lane2007). The majority of evidence suggests thatTP53-mediated tumor suppression is governedby transcriptional regulation; therefore, un-derstanding the critical TP53 gene targets andmechanisms of their transcriptional regulationis a key objective.

TP53-mediated transcriptional regulationvaries according to the type of stress stimulusand type of cell, so that appropriate correctiveprocesses can be implemented. For example,minor DNA damage may institute cell-cyclearrest and activate DNA-repair mechanisms,whereas stronger TP53-activating signals in-duce senescence or apoptosis. Accordingly, theTP53 transcriptional response varies dependingon the nature of the activating signal and thetype of cell; the detailed mechanisms underly-

Stress-induced TP53 activation

Mdm2

TP53

Ub

Ub

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ATMATRCHK1 CHK2P14/ARF

(P19/ARF)

Hdm2(Mdm2)Pirh2MdmXCop-1

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Oncogeneexpression

Metabolicdysfunction

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A

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TP53

Ac

Ac P

P Context-specifictranscriptional

activation

Hdm2 (Mdm2) CDNA damage

Nutrient deprivationOxidative stress

??

Basal TP53 activity

Figure 1. Appropriate activation and feedback control of TP53 activity is critical to effective tumor suppression.(A) In the absence of a TP53-activating signal, TP53 protein levels are maintained at low levels in most cell typesby the E3 ubiquitin ligase, MDM2 (HDM2), which ubiquitinates (Ub) TP53 and targets it for degradation by theproteosome. (B) The TP53 protein may also control gene expression in the absence of an activating stimulus, forexample, by transcriptional repression. The extent to which basal TP53 activities contribute to the tumor-suppressor function is not known. (C) Stress stimuli, such as oncogene expression, DNA damage, and metabolicdysfunction, rapidly lead to TP53 protein accumulation and activation; this is in part owing to inhibition ofMDM2 (HDM2), thus preventing TP53 ubiquitination and proteosomal degradation. Following activation, theTP53 protein acts as a sequence-specific transcription factor directing the expression of a large number of targetgenes, which are considered the primary determinants of the tumor-suppressor response. The specific mode ofthe TP53 response is influenced by extensive posttranslational modification, including acetylation (Ac) andphosphorylation (P).

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ing these differences in transcriptional induc-tion of target genes remain unknown. However,unprecedented insight into this process has beengained through the analysis of TP53 proteinDNA binding and transcriptional regulation us-ing next-generation techniques, such as chro-matin immunoprecipitation (ChIP) DNA andRNA sequencing. The number of known or sus-pected TP53 target genes has increased into thethousands with dramatic differences in tran-scriptional responses observed among differentcell types, different TP53-inducing stress stim-uli, and varying time points following TP53 ac-tivation (Allen et al. 2014). These studies paintan increasingly complex picture of the modesby which TP53 can regulate gene expression.For example, before TP53 activation, a subset

of target genes is transcriptionally repressed bythe TP53 protein (Allen et al. 2014). More re-cently appreciated functions of the TP53 proteininclude widespread binding and modulation ofenhancer regions throughout the genome andtranscriptional activation of noncoding RNAs(He et al. 2007; Younger et al. 2015). Interesting-ly, the TP53-activated long noncoding RNA,lincRNA-p21, exerts widespread suppressionof gene expression (Huarte et al. 2010). The listof proposed TP53 target genes is vast and theyare known to influence diverse cellular pro-cesses, including apoptosis, cell-cycle arrest,senescence, DNA-damage repair, metabolism,and global regulation of gene expression, eachof which could potentially contribute to its tu-mor-suppressor function (Fig. 2).

Apoptosis SenescenceG1 cell-

cycle arrestTP53

regulation

PmlPai-1

Cdkn1aE2f7

Puma/Bbc3Noxa/Pmaip1

BaxApaf-1

FasmiR34Zmat3

Cdkn1aBtg2PtprvPml

Cav1miR34Mdm2

MetabolismDNA-damage

repair

SLC7A11TIGARSco-2

Glut1/3/4DRAM

Adora2BSesn1/2

Gls2

Ddb2PolHXpcPolkMgmtErcc5Msh2Fancc

???

Acute DNA-damage response

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mRNAmiRNA lincRNA

G2/M cell-cycle arrest

Emergingfunctions

TP53

lincRNA-p21

Transcriptionregulation

Cdkn1a14-3-3σReprimoGadd45

Figure 2. The TP53 protein exerts its tumor-suppressor function as a sequence-specific transcription factor.Following activation, the TP53 protein directs the expression of a large number of genes encoding mRNA,miRNA, and lincRNAs that orchestrate a variety of cellular processes. In addition, TP53 may have as yetundetermined effector functions that are important for tumor suppression. It is increasingly apparent that asingle effector function is inadequate to explain the potency and complexity of TP53’s tumor-suppressorfunction. In contrast, specific effector functions may be more or less important depending on the contextand multiple effector pathways are likely to collaborate and synergize in the prevention and suppression oftumor formation. Selected TP53-regulated murine genes are shown with their associated cellular processes(some genes may impact on various pathways, e.g., CDKN1a [p21], which is critical for G1 cell-cycle arrest andcell senescence).



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Insight into the critical TP53 transcriptionaltargets has been gained from genetic mousemodels expressing transcriptionally defectivemutant TP53 proteins. Interestingly, a partiallytransactivation defective TP53 protein, denotedTP5325,26 (Brady et al. 2011), can only activatea limited number of TP53 target genes and isunable to induce apoptosis, cell-cycle arrest,or senescence, yet it retains the ability to sup-press tumor formation. Complementary find-ings have been observed in a different mousemodel, in which key lysine residues of theTP53 protein, which are modified by acetyla-tion during posttranslational activation, havebeen mutated to arginine, denoted TP533KR

(Li et al. 2012). Similar to the TP5325,26 mutant,the mutant TP533KR protein is unable to activatetarget genes that mediate apoptosis, cell-cyclearrest, and cell senescence, yet it still retains theability to suppress tumor development. Exami-nation of these mutant strains of mice revealedpreserved regulation of several TP53 responsegenes involved in DNA-damage repair and me-tabolism, implicating a potentially critical rolefor these processes in tumor suppression. Atpresent, the search for the critical TP53 tumor-suppressor transcriptional targets is underwayin earnest.

KEY EFFECTOR FUNCTIONS FORTUMOR SUPPRESSION

Apoptosis

Apoptosis was one of the earliest identifiedcomponents of the TP53-mediated tumor-sup-pressor response (Yonish-Rouach et al. 1991).Induction of apoptosis is among the most ex-tensively studied cellular processes activated bythe TP53 protein and has been the focus ofmuch of the investigation into its tumor-sup-pressor effect. Impaired apoptosis is a cardinalfeature of malignancy and genetic alterationsthat result in evasion from apoptotic celldeath markedly accelerate tumor development(Vaux et al. 1988; Strasser et al. 1990; Czabotaret al. 2014). Multiple TP53 target genes havebeen implicated in TP53-mediated inductionof apoptosis: Puma, Noxa, Bax, Apaf1, Fas,Tnfrsf10B/DR5, miR34, TP53AIP1, Pidd, Pig3,

Zmat3, and Siva. Among these target genes,Puma, Noxa, Bax, and Apaf-1 play critical rolesin the intrinsic (also called BCL-2-regulated ormitochondrial) apoptotic pathway (Youle andStrasser 2008; Strasser et al. 2011), whereas Fasand Tnfrsf10B/DR5 encode for members ofthe tumor necrosis factor receptor (TNFR) fam-ily (FAS/APO-1/CD95 and TRAIL-R/DR5)that can trigger the death receptor (also calledextrinsic) apoptotic pathway (Strasser et al.2009). Of all these TP53 target genes, only theproapoptotic BH3-only BCL-2 family mem-bers PUMA and NOXA have been validated bystudies of gene-targeted mice to be essential forTP53-mediated apoptosis (Jeffers et al. 2003;Shibue et al. 2003; Villunger et al. 2003; Micha-lak et al. 2008). Although the Bax and Apaf-1genes are also direct TP53 targets (Riley et al.2008), TP53-deficient cells still express these ef-fectors of apoptosis. Therefore, their inductionlikely serves to amplify TP53-mediated apopto-sis signaling. The miR34 family of microRNAs isa TP53 target (He et al. 2007) predicted to exertbroad antioncogenic effects through the post-transcriptional regulation of a variety of genesthat not only sensitize to apoptosis, for example,by down-regulation of BCL-2 (Bommer et al.2007), but also through regulation of cell-cycleprogression and differentiation. Surprisingly,however, mice that are deficient of all miR34family members are not susceptible to sponta-neous or oncogene-induced tumor develop-ment (Concepcion et al. 2012). Importantly,the death receptor apoptotic pathway is dispen-sable for TP53-induced apoptosis (Newton andStrasser 2000). However, TP53-mediated in-duction of Fas and Tnfrsf10B/DR5 expressionmay serve to sensitize stressed cells to the deathreceptor ligands, FASL and TRAIL, and it hasbeen proposed that this could be exploited forcancer therapy (Ashkenazi 2008).

The role of TP53-mediated apoptosis inpreventing oncogene-driven cancer develop-ment has been defined using the Em-Myc trans-genic mouse model (Adams et al. 1985). Herethe immunoglobulin heavy chain gene enhanc-er (Em) has been juxtaposed to the c-Myc onco-gene, resulting in deregulated c-MYC expressionand, consequently, the rapid development of

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pre-B and B-cell lymphomas. In the Em-Mycmouse model, spontaneous inactivation of theTP53 pathway, most frequently through muta-tions in Tp53 itself, is seen in �20% of lympho-mas (Eischen et al. 1999; Schmitt et al. 1999;Michalak et al. 2009), indicative of its criticalrole in this setting. Accordingly, inactivation ofTP53 function markedly accelerates MYC-driv-en lymphoma development (Schmitt et al.1999; Michalak et al. 2009). Strikingly, completedeletion of the Tp53 gene using CRISPR/Cas9targeting in Em-Myc hematopoietic stem/pro-genitor cells (HSPC) results in the rapid devel-opment of lymphoma with a median latency ofonly 29 d (Aubrey et al. 2015) as compared withnontargeted Em-Myc HSPC that give rise tolymphoma with a mean latency of .110 d.The specific requirement for individual TP53apoptotic transcriptional targets in the tumor-suppressor function has been dissected usingthe Em-Myc mouse model where loss of BAX(Eischen et al. 2001; Dansen et al. 2006),PUMA, and NOXA (Hemann et al. 2004; Mi-chalak et al. 2009) can each accelerate lympho-ma development, although not to the same ex-tent as complete loss of TP53 function. Thissuggests critical roles for additional pathwaysin tumor suppression during MYC-driven lym-phoma development.

Interestingly, mice engineered to harboronly specific gene knockout of the TP53 apo-ptotic targets Puma (Jeffers et al. 2003), Noxa(Villunger et al. 2003), Bax (Knudson et al.2001), or even combined loss of Puma/Noxa/p21 (Valente et al. 2013) do not display a pro-pensity for tumor formation. Thus, in the ab-sence of constitutive oncogenic stress, the com-bined knockout of the major TP53-dependentmediators of apoptosis (PUMA and NOXA)and the major mediator of G1/S cell-cycle arrestand cell senescence (p21) does not recapitulatethe tumor predisposition observed in Tp532/2

mice. Apoptosis clearly plays a critical role intumor suppression; however, additional path-ways must be disabled to fully recapitulate theeffect from complete loss of TP53. Furthermore,these studies show that the animal model inwhich TP53 functions is examined will likelyinfluence the experimental findings. Although

PUMA, NOXA, and BAX are important medi-ators of TP53-induced apoptosis, there may beadditional proapoptotic effector mechanismsthat have yet to be fully defined. For example,the proapoptotic BH3-only protein BIM maybe induced indirectly by TP53 and contributeto the killing of tumor cells by DNA-damage-inducing chemotherapeutic drugs (Happo et al.2010). Importantly, there is substantial overlapbetween the regulation of apoptotic cell deathand other pathways, such as DNA-damage re-pair and metabolism; thus, the role of apoptosisin tumor suppression may be intertwined withother TP53-dependent effectors.

Cell-Cycle Regulation and DNA-Damage Repair

Cancer is a disease that results from the progres-sive acquisition and accumulation of geneticmutations (Hanahan and Weinberg 2011), andthe TP53 protein, as the “guardian of the ge-nome” (Lane 1992), has a salient role in main-taining genomic integrity and opposing thisprocess. The TP53 protein plays an intimaterole in the cellular response to DNA damage.It is critical to both the acute phase responseinvolving cell-cycle arrest, senescence, and apo-ptosis as well as long-term surveillance mecha-nisms for maintaining multiple DNA-damage-repair mechanisms, such as nucleotide excisionrepair, base excision repair, and nonhomolo-gous end-joining (Sengupta and Harris 2005).

In many cells, the initial TP53-mediated re-sponse to acute DNA damage is the induction oftransient G1 cell-cycle arrest, which allows timefor the detection and repair of DNA damagebefore replication of the genome in S phaseand subsequent cell division. The TP53 proteinalso exerts checkpoint control during the G2/Mtransition, at which time DNA replication hasalready occurred and cells prepare to undergomitotic cell division (Taylor and Stark 2001), atime when failed detection and repair of dam-aged DNA may be most catastrophic (e.g., re-sulting in aneuploidy). Both cell-cycle check-points are critical to maintaining genomicintegrity and the requirement for TP53-medi-ated cell-cycle arrest in maintaining genomic



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stability has been shown experimentally (Bar-boza et al. 2006). The key mediator of TP53-induced G1 cell-cycle arrest is thought tobe CDKN1a (p21), as shown by cells fromCdkn1a2/2 mice that show impaired G1 cell-cycle arrest in response to DNA damage andTP53 activation (El-Deiryet al. 1993; Brugarolaset al. 1995; Deng et al. 1995). Given the integralrole of cell-cycle arrest in DNA repair, CDKN1ahas been proposed to contribute to TP53-medi-ated tumor suppression. However, mice thatlack CDKN1a (p21) are not prone to spontane-ous tumor formation (Deng et al. 1995; Valenteet al. 2013). Additional TP53 transcriptionaltargets also contribute to G1 phase cell-cyclearrest including, but not limited to, the promye-locytic gene (Pml), protein tyrosine phospha-tase receptor type-V gene (Ptprv), Caveolin-1(Cav1) (Galbiati et al. 2001), and Btg2 (Rouaultet al. 1996). In addition, other TP53 targets spe-cifically instigate cell-cycle arrest at the G2/Mcheckpoint, including the growth-arrest andDNA-damage-inducible 45 a gene (Gadd45a),Reprimo, and the 14-3-3s protein (Taylor andStark 2001). The roles of GADD45a, PTPRV,PML, and CAV1 have been examined indi-vidually through the generation of knockoutmice but none of these animals spontaneouslydevelop cancer (Hollander et al. 1999; Razani etal. 2001; Rego et al. 2001; Doumont et al. 2005).However, similar to other candidate TP53 tu-mor-suppressor transcriptional targets, theirdeficiency can accelerate tumor formation un-der conditions of specific oncogenic stress (Ca-pozza et al. 2003; Tront et al. 2010).

TP53-induced cell-cycle arrest is thoughtnecessary to allow for appropriate DNA-repairprocesses to occur (Barboza et al. 2006). Pre-cancerous lesions are characterized by the ac-cumulation of DNA damage and consequentactivation of the TP53-mediated DNA-damageresponse (Bartkova et al. 2005; Gorgoulis et al.2005). The acquisition of mutations duringtumor initiation occurs through a variety ofmechanisms including mutations and epigenet-ic modifications followed by propagation ofthese alterations owing to defective DNA-dam-age repair mechanisms. The TP53 protein playspivotal roles in all of these processes and, in

keeping with the importance of TP53 in main-taining genomic stability, cells from Tp532/2

mice as well as TP53-defective human cancersare characterized by widespread genomic alter-ations. In line with this, TP53 has a large num-ber of direct transcriptional targets that mediateDNA-repair pathways, including Polk, Mgmt,Fancc, Ercc5, Xpc, Ddb2, Gadd45a, Msh2, andPolH (Allen et al. 2014; Bieging et al. 2014). Thecentral role of genomic instability during theevolution of thymic lymphomas in Tp532/2

mice has been directly observed over time,where defective DNA repair results in a veryhigh rate of gene copy number variations, in-cluding chromotrypsis-like events, which drivethe accumulation of the cooperating genetic le-sions required for malignant transformation(Dudgeon et al. 2014). This supports the notionthat genomic instability is a key driver of cancerdevelopment in the absence of the TP53 protein.

In certain cell types, activation of the TP53protein can result in the induction of apoptosisresulting in the elimination of irreversibly dam-aged cells. However, the acute DNA-damage re-sponse has been largely excluded from a role inthe TP53 tumor-suppressor function throughmultiple lines of investigation (Christophorouet al. 2006; Brady et al. 2011; Li et al. 2012).The role of the acute DNA-damage response intumor suppression was evaluated using timedrestoration of TP53 protein in Tp532/2 micefollowing g-irradiation to induce thymic lym-phoma formation. Remarkably, transient TP53restoration during the acute DNA-damage re-sponse did not produce a tumor-suppressoreffect (Christophorou et al. 2006). In contrast,transient restoration of TP53 function that wasdelayed until after the acute DNA-damage re-sponse had ended, at a time when there wasno discernable cell-cycle arrest or apoptosis,was sufficient for tumor suppression. Further-more, the delayed tumor-suppressor functionobserved is dependent on p19/ARF, implicatingoncogene-mediated TP53 activation in nascentneoplastic cells in this response. This is furtherconfirmed through studies of transcriptionallydefective and acetylation defective mutant TP53proteins that are unable to activate the acuteDNA-damage response yet retain potent tu-

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mor-suppressor function (Brady et al. 2011;Li et al. 2012). Therefore, the acute pathologi-cal DNA-damage response appears to be dis-pensable for tumor suppression, a remarkablefinding that also has major implications for can-cer therapy.

The consequences of oncogene overexpres-sion are twofold in the setting of DNA damageand TP53-mediated tumor suppression. First,acquired mutations may result in the activationof oncogenes, and cells expressing oncogenescan be selected for through enhanced prolifera-tion and cell survival. Second, chronic oncogeneactivation drives abnormal cell growth, therebyincreasing the risk of acquiring additional DNAlesions that may activate further oncogenes orinactivate tumor-suppressor genes (Halazonetiset al. 2008). TP53 may be purposed to eliminateor growth-arrest cells marked by oncogene over-expression, which is intimately connected withDNA damage, deregulated cell proliferation,and metabolic deregulation.

Senescence

Induction of cell senescence was first shownto play a critical role in TP53-mediated tumorsuppression in a mouse model of erythroleuke-mia (Metz et al. 1995). Moreover, restoration ofTP53 function in established solid-organ tu-mors (driven by loss of TP53) in vivo leads tothe induction of cellular senescence in associa-tion with tumor regression (Ventura et al. 2007;Xue et al. 2007). Cellular senescence is a distinctcell state involving permanent cell-cycle arrestof cells that remain viable and metabolically ac-tive, which is characterized by a discrete tran-scriptional profile (Shay and Roninson 2004).The TP53 protein controls cellular senescenceby activating a number of transcriptional targetsthat include Cdkn1a, Pml, Pai1, and E2f7 (Pear-son et al. 2000; Kortlever et al. 2006; Aksoy et al.2012), some of which (e.g., Cdkn1a) are nota-ble for additional function in cell-cycle regula-tion. Senescence is often associated with, andis thought to suppress, premalignant lesionspreventing their progression to overt malignan-cy (Collado et al. 2005; Mooi and Peeper 2006).TP53-mediated induction of cell senescence

was shown to be critical to preventing malignanttransformation in a mouse model of BRAF-driven pulmonary adenoma (Dankort et al.2007). Moreover, in a study examining the func-tional interdependence of defects in PTEN andTP53 in the development of prostate carcinoma,TP53-mediated senescence was required to pre-vent cancer development in the setting of PTENdeletion (Chen et al. 2005). It remains to beexamined whether complete loss of all targetgenes implicated in TP53-mediated senescencecan recapitulate the spontaneous tumor devel-opment seen in Tp532/2 mice and whether thestrong association between senescence and tu-mor suppression is causal or whether this is anassociation with other TP53-mediated effects.

Metabolism

The rapid proliferation of cells, anabolic growth,and metabolic stress that typifies neoplasticdisease requires substantial metabolic repro-gramming (Hanahan and Weinberg 2011). Fur-thermore, metabolic deregulation not only im-pacts on energy production and cell growth butalso influences additional processes importantto sustained cancer growth, such as macromo-lecular biosynthesis, epigenetic regulation, andantioxidant pathways (Cairns et al. 2011; Wardand Thompson 2012). The TP53 protein is acritical regulator of cellular metabolism andmany of the aforementioned processes affectedby metabolic stress (Berkers et al. 2013).

The best-characterized description of can-cer-associated metabolic reprogramming is theWarburg effect, whereby glucose is predomi-nantly metabolized by glycolysis rather than ox-idative phosphorylation, as normally occurs un-der aerobic conditions (Warburg 1956). TP53activation stimulates oxidative phosphorylationand inhibits glycolysis, both of which opposethe Warburg effect. The TP53 protein can regu-late the expression of several glucose transport-ers, including GLUT1, GLUT3, and GLUT4(Schwartzenberg-Bar-Yoseph et al. 2004; Ka-wauchi et al. 2008), which diminishes glycolysisthrough impaired glucose uptake. TP53 alsotransactivates the TP53-induced glycolysis andapoptosis regulator gene (TIGAR), which en-



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codes a fructose phosphatase enzyme that in-hibits glycolysis and increases production ofNADPH (Bensaad et al. 2006). NADPH is im-portant for the scavenging of reactive oxygenspecies (ROS), and this antioxidant effect ofTIGAR confers a prosurvival function in thesetting of ROS-mediated cell death. However,TIGAR knockout mice do not show spontane-ous tumor formation (Cheung et al. 2013) and,in some contexts, TIGAR deficiency actuallyimpedes tumor development (Bensaad et al.2006). TP53 also directly stimulates mitochon-drial oxidative phosphorylation through tran-scriptional activation of the gene-encoding syn-thesis of cytochrome c oxidase 2 (Sco2) (Matobaet al. 2006). Interestingly, dysregulated oxidativephosphorylation has been observed in cells frompatients with Li–Fraumeni syndrome, whichis attributed partly to altered Sco-2 expression(Wang et al. 2013).

The strict regulation of cellular antioxidantmechanisms is critical to maintaining intra-cellular signaling pathways and avoiding ROS-associated toxicity. Therefore, dysregulationof these processes can contribute to cancer de-velopment (Finkel 2003). Genes encoding en-zymes with antioxidant functions, includingGls2, Sestrin 1, and Sestrin 2, have been identi-fied as TP53 transcriptional targets (Budanovet al. 2004; Hu et al. 2010), defining a mecha-nism by which TP53 can regulate oxidant sig-naling and manage oxidative stress. Interest-ingly, treatment of Tp53 knockout mice withantioxidant therapy was reported to delay theonset of tumor formation, implicating a role forlimiting the ROS accumulation in TP53-medi-ated tumor suppression (Sablina et al. 2005).

Cancer-associated metabolic stress andhypoxia can activate distinct cell death pathwaysthrough a variety of mechanisms, including theintrinsic apoptotic pathway (Czabotar et al.2014). TP53 can modulate metabolic stress-induced cell death through a number of mech-anisms. For example, the TP53 protein drivesexpression of the ADORA2B gene, which candetect nutrient availability and sensitize cellsto PUMA-mediated apoptotic cell death (Longet al. 2013). In addition, a recently describedform of iron-dependent, nonapoptotic cell

death, denoted ferroptosis, is initiated underconditions of metabolic stress and accumulatedROS (Dixon et al. 2012). It has been proposedthat TP53 mediates tumor suppression throughtranscriptional repression of the SLC7A11 gene,which encodes a cystine/glutamate antiporterthat diminishes cellular predisposition to fer-roptosis (Jiang et al. 2015).

Finally, autophagy is another TP53-regu-lated metabolic process that may contribute totumor suppression (Maiuri et al. 2010; Kenzel-mann Broz et al. 2013). Autophagy enables cellsto adapt and survive in conditions of limitingnutrient availability by recycling intracellularcontents, such as damaged proteins and or-ganelles for the purpose of liberating energyand metabolites to maintain cellular integrity(Mathew and White 2011). Autophagy may fur-ther impact on tumor suppression by affectingapoptotic pathways and genomic stability. TP53regulates autophagyat multiple levels (Feng et al.2005) by transactivating a large number of genes(Kenzelmann Broz et al. 2013), including thegenes encoding damage-associated autophagymediator (DRAM) (Crighton et al. 2006) andULK1 (Gao et al. 2011). Interestingly, siRNA-mediated knockdown of DRAM was shownto reduce TP53-dependent apoptosis (Crightonet al. 2006).

EMERGING TP53 FUNCTIONSAND TUMOR SUPPRESSION

New components of the TP53 response contin-ue to emerge and many of these have been im-plicated in tumor suppression (Bieging et al.2014; Hager and Gu 2014). These include rolesfor TP53 in stem-cell function, differentiation,cellular invasion, and metastasis, as well as reg-ulation of the immune response and the tumormicroenvironment. For example, in a mousemodel of hepatocellular carcinoma, TP53 wasshown to influence the microenvironment andimmune response via a non-tumor-cell-auton-omous mechanism, which impacted the rate oftumor expansion and aggressiveness (Lujambioet al. 2013). These emerging functions haveas yet undetermined roles in tumor suppres-sion; however, they highlight the increasingly

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complex picture of the role of TP53 in cancerbiology.

In addition to newly identified functionsfor the TP53 protein, novel approaches to un-derstanding the mechanisms of tumor suppres-sion are emerging. Cell competition has recentlybeen established as a bona fide mechanism fortumor suppression (Martins et al. 2014) when itwas shown that disruption of normal cell com-petition in the thymus leads to the formation ofacute T-lymphoblastic leukemia. The conceptof cell competition provides a view of the overallfitness of cells as they compete within a largerpopulation of cells, accounting for various cel-lular attributes as well as context-dependentfactors. In studies of hematopoietic progenitorcells, the TP53 protein was shown to mediatecell competition (Bondar and Medzhitov 2010),raising the possibility that cell competitionmay be an important framework within whichto approach the question of TP53-mediated tu-mor suppression.

DISTINCTIONS BETWEEN HUMAN CANCERAND MOUSE MODELS

It is important to recognize a number of keydistinctions between findings from mousemodels and human disease. In human cancer,inactivation of the TP53 gene almost always oc-curs by acquisition of a missense mutation rath-er than deletion of the TP53 gene. Furthermore,these mutations frequently result in a singleamino acid substitution and the production ofa stable, overexpressed TP53 protein that canactively contribute to tumor development andgrowth over and above the consequences of los-ing wild-type TP53 function alone (Freed-Pas-tor and Prives 2012). In addition, the initialacquisition of Tp53 mutations is usually fol-lowed by loss of heterozygosity, which typicallyinvolves large deletions of the short arm of chro-mosome 17 (17p). The large chromosomal de-letion results in the loss of several additionalgenes and this raises the possibility that coop-erating lesions on 17p may contribute to humancancers. For example, a gene encoding a com-ponent of the RNA polymerase II complex,POLR2A, is almost always codeleted in human

cancers with the TP53 gene, and this has func-tional impact on the resulting tumor (Liu et al.2015). These are important features of humancancer that are inextricable from the questionof understanding how loss or mutation of TP53leads to the development of cancer.

CONCLUDING REMARKS

The tumor-suppressor function of the TP53protein is likely to be mediated through a num-ber of collaborating effector functions ratherthan through a single pathway or single tran-scriptional target. Understanding how thesemechanisms work together will require creativeapproaches to investigation that take into ac-count the combinatorial nature and complexityof the TP53 response as well as considerationof its functioning in normal cellular processes.It is an intriguing question as to whether theprimary purpose of the TP53 protein is tumorsuppression or whether this is a secondary man-ifestation of its many important roles in normalbiology. For example, the importance of theTP53 protein in maintaining genomic stabilityextends beyond the prevention of cancer tobeing a basic requirement for sustainable lifethat ensures an organism’s genetic material istransmitted faithfully to subsequent generations(Jackson and Bartek 2009; Kerr et al. 2012) andspeaks to the evolutionary conservation of theTp53 family of genes from the earliest multicel-lular organisms to humans (Belyi et al. 2010;Lane et al. 2010). Another important consider-ation is that TP53 contributes to normal cellularprocesses that may also be important in estab-lished tumors. For example, TP53 facilitatesadaptation to some forms of metabolic stress,such as serine deprivation, whereby Tp532/2

cells are actually disadvantaged (Maddockset al. 2013). As such, the complete loss of TP53function during cancer initiation may not beentirely advantageous and such vulnerabilitiesmay be exploited for treatment of TP53-defi-cient cancers. Understanding the role of TP53in tumor suppression remains one of the mostexciting and important biological questionsthat promises exciting advances for the next30 years of TP53 research.



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ACKNOWLEDGMENTS

The authors thank Drs. Marco J. Herold, DanielH.D. Gray, Jerry M. Adams, Suzanne Cory, andAna Janic for insightful discussions and advice,and Cameron Wells and Rachel Bucknall forassistance with graphic design. This work issupported by a Leukaemia Foundation NationalResearch Program Clinical PhD Scholarship(B.J.A.), a Kay Kendall Leukaemia Fund In-termediate Fellowship (KKL331 to G.L.K.),a National Health and Medical Research Coun-cil, Australia, Program Grant 1016701 (A.S.)and Fellowship 1020363 (A.S.), Project Grant1086291 from the National Health and Medi-cal Research Council, Australia (G.L.K.), a Can-cer Council Victoria Grant-in-Aid 1086157(G.L.K), and a Leukemia and LymphomaSociety SCOR Grant 7001-13 (A.S.). Thiswork is made possible through Victorian StateGovernment Operational Infrastructure Sup-port and Australian Government NationalHealth and Medical Research Council Indepen-dent Research Institutes Infrastructure SupportScheme.

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2016; doi: 10.1101/cshperspect.a026062Cold Spring Harb Perspect Med Brandon J. Aubrey, Andreas Strasser and Gemma L. Kelly Tumor-Suppressor Functions of the TP53 Pathway

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and James G. JacksonCrystal A. Tonnessen-Murray, Guillermina Lozano

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The Inherited p53 Mutation in the Brazilian

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Yoav Shetzer, Alina Molchadsky and Varda Rotter

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